Baseline Gene Expression Signatures in Monocytes from Multiple Sclerosis Patients Treated with Interferon-beta

Abstract

BackgroundA relatively large proportion of relapsing-remitting multiple sclerosis (RRMS) patients do not respond to interferon-beta (IFNb) treatment. In previous studies with peripheral blood mononuclear cells (PBMC), we identified a subgroup of IFNb non-responders that was characterized by a baseline over-expression of type I IFN inducible genes. Additional mechanistic experiments carried out in IFNb non-responders suggested a selective alteration of the type I IFN signaling pathway in the population of blood monocytes. Here, we aimed (i) to investigate whether the type I IFN signaling pathway is up-regulated in isolated monocytes from IFNb non-responders at baseline; and (ii) to search for additional biological pathways in this cell population that may be implicated in the response to IFNb treatment.MethodsTwenty RRMS patients classified according to their clinical response to IFNb treatment and 10 healthy controls were included in the study. Monocytes were purified from PBMC obtained before treatment by cell sorting and the gene expression profiling was determined with oligonucleotide microarrays.Results and discussionPurified monocytes from IFNb non-responders were characterized by an over-expression of type I IFN responsive genes, which confirms the type I IFN signature in monocytes suggested from previous studies. Other relevant signaling pathways that were up-regulated in IFNb non-responders were related with the mitochondrial function and processes such as protein synthesis and antigen presentation, and together with the type I IFN signaling pathway, may also be playing roles in the response to IFNb.

Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

“…These data indicate that single risk genes involved in IFN signaling may be dysregulated in MS, and that this phenomenon is not necessarily conserved throughout all MS stages, raising the hypothesis that Interferome may be characterized by transcriptomic changes specific to disease type. Among several reports indicating transcriptional dysregulation induced by IFN-beta treatment in blood cells of MS patients 10 – 13 , a couple of studies suggest that expression of some type I IFN regulated genes may be dysregulated at baseline and correlate with biological response to IFN-beta therapy 14 – 16 . No study has however provided the systematic analysis of Interferome in treatment-naïve MS subjects at distinct stages of disease.…”

An interferon-β-resistant and NLRP3 inflammasome–independent subtype of EAE with neuronal damage

“…When relative expression levels to VCAM1 were calculated ( VCAM1 is expressed in monocytes (Expression Atlas by EMBL-EBI) and is not differentially expressed between IFNβ-responder and nonresponder RRMS patients 21 ), the data showed that relative mRNA expression of CXCR2 , CXCR1 , and LTBR were significantly higher in IFNβ-responders than nonresponders (Figure 4c). Here, the two-thirds of non-responders showed comparable gene expression levels to responders.…”

Immune and Epstein-Barr virus gene expression in cerebrospinal fluid and peripheral blood mononuclear cells from patients with relapsing-remitting multiple sclerosis

“…To date, no relevant differences in gene expression have been reproducibly demonstrated in whole blood cells or PBMC when comparing MS patients and controls, patients in clinical relapse and remission, or patients with different disease courses [ 15 – 21 ]. A higher type-1 IFN signature has been detected in the blood, specifically in monocytes [ 60 , 61 ], of a subset of treatment naïve patients with RRMS and has been associated with a poor response to IFN-β [ 60 , 62 , 63 ]. Recently, differences in PBMC gene expression profiles were detected between male and female patients with RRMS [ 44 ], although results interpretation is complicated by different treatment regimens.…”